Aliskiren hemifumarate (Formula I) [CAS Registry Number: 173334-58-2], having the chemical name: (2S,4S,5S,7S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxyl)phenyl]octanamide hemifumarate [C30H53N3O60.0.5 C4H4O4] and is depicted structurally as below:

Aliskiren as renin inhibitor is generally known in the art. It is useful for the treatment of hypertension and its hemifumarate salt is commercially available under the trade names Tekturna® and Rasilez®.
Synthesis of Aliskiren and its related compounds are referred in U.S. Pat. No. 5,559,111, while pharmacological actions, pharmacokinetics and clinical studies of Aliskiren and its related compounds are referred to in Lindsay, K. B. et. al., J. Org. Chem., Vol. 71, pp 4766-4777 (2006) and in Drugs of the Future, Vol. 26, No. 12, pp 1139-1148 (2001).
As Aliskiren comprises 4 chiral centers, the synthesis of the diastereomerically and enantiomerically pure compound is quite challenging. Therefore, synthetic routes that allow more convenient synthesis of this complex molecule are welcome.
The main drawback in the product patent route (U.S. Pat. No. 5,559,111) is the deoxygenation of benzylic hydroxy (or as acyloxy) by hydrogenolysis using palladium catalyst which results in the formation of complex mixture of the products e.g. pyrrolidine derivative (derived from the reduction of azide followed by cyclization) as a major product and desired deoxygenated product along with only reduced product. The similar results were also observed even after opening the lactone ring. This problem has also been encountered during deoxygenation of benzylic hydroxy (or as acyloxy) even after protecting the azide nitrogen as carbamate to provide alkoxy carbonyl protected pyrrolidine as an exclusive product (also reported in literature). The incomplete reaction, use of excess metal catalyst, longer reaction time and purification of intermediates by column chromatography leads to poor yield of the final product and in turn it makes the process industrially unacceptable.
U.S. Pat. No. 6,683,206 refers to the process for the preparation of intermediate of Aliskiren hemifumarate, wherein deoxygenation of benzylic hydroxyl group is carried out by conversion of said hydroxyl group into the good leaving group, which is further removed by formation of conjugated double bond. Such deoxygenation methodology demands subsequent catalytic asymmetric hydrogenation, which requires expensive metal catalyst such as ruthenium, rhodium and iridium.
The major drawback of the process described in U.S. Pat. No. 6,800,769 is that all intermediates are reported as an oily mass, no intermediate is isolable as solid material. Purification of those intermediates is only possible by column chromatography, which is slow, tedious, lengthy and not industrially feasible. It is not desirable to perform column chromatography at all the intermediate stages and under such circumstances, impurities are being carried forward till the final API i.e. Aliskiren hemifumarate. Purification at the final stage to remove the various impurities affects the yield and in turn significantly increases the cost of API.
The drawbacks of the above mentioned prior art processes for the preparation of Aliskiren and its hemifumarate salt are low yield, accompanied with a number of side reactions, use of excess/expensive metal catalyst, longer reaction time and significant amount of various impurities.
Nevertheless, there still remains a need for industrial friendly, economical and efficient manufacturing process for the preparation of Aliskiren hemifumarate that is free from above mentioned drawbacks and achieves high yield and high degree of purity in environmental friendly condition.
The problem has been solved by the applicant by providing novel process and novel intermediates allowing a convenient and efficient synthesis of Aliskiren and pharmaceutically acceptable salts thereof, preferably Aliskiren hemifumarate.